tbuckley/cabot-search huggingface dataset:
Incidence and severity of neutropenia in patients treated with cyclin-dependent kinase 4/6 inhibitors (CDKi) for metastatic breast cancer.
Authors: Anmol Singh, Sharon H. Giordano, Ning Zhang, Mariana Chavez Mac Gregor, Hui Zhao
Journal: Journal of Clinical Oncology (2022)

e13036 Background: Palbociclib (P), ribociclib (R), and abemaciclib (A) are FDA approved CDKi used in combination with endocrine therapy for first- and second-line treatment of metastatic breast cancer. Neutropenia is a commonly encountered adverse effect with these agents. This analysis aimed to identify the incidence and severity of neutropenia in patients receiving CDKis. Methods: This retrospective, observational study used administrative data from the Optum’s de-identified Clinformatics® Data Mart Database (January 2016-June 2020) to identify patients treated with P, R, or A and who had at least two ICD-9 or ICD-10 diagnosis codes for breast cancer separated by &gt;30 days. Using claims, neutropenia was defined as either one inpatient diagnosis code or 2 outpatient diagnosis codes from the time of the patient’s first CDKi prescription claim to the time of the last claim plus 42 days. For the subset of patients who had laboratory results during their period of treatment with CDKi, neutropenia was defined as an absolute neutrophil count (ANC) &lt;1500 and severe neutropenia as ANC &lt;500. Descriptive statistics and logistic regression models were used to characterize the population and to identify risk factors for development of neutropenia. Results: Of the total of 8,158 included patients, 82% were treated with P, 4.1% with R, 7.5% with A, and 6.4% with more than one CDKi. Patient age ranged from 28 to 91 years (median= 68 years). Median follow up from initiation of CDKi until the end was 194 days. 17.5% patients had ICD claims indicating neutropenia but only 1.6% were hospitalized with a diagnosis of neutropenia. Neutropenia codes were observed in 31.6% patients treated with P, 24.6% patients treated with R, and 15.6% patients treated with A. Among the 4766 patients who had laboratory results, 81% were treated with P, 4% with R, 7% with A, and 8% with more than one CDKi. 31.6% of patients had neutropenia defined by ANC &lt; 1500. Severe neutropenia was seen in 10.8% of patients treated with P, 5.7% of those treated with R, and 5% of those treated with A. In a logistic regression model among the patients with lab results, patients treated with P had increased odds of neutropenia compared to those treated with A (OR 1.84, 95% CI 1.40-2.43) but patients treated with R vs A did not (OR 1.46, 95% CI 0.95-2.25). Asian and Hispanic patients had higher odds of neutropenia (OR 1.7, 95% CI 1.2-2.4, OR 2.1, 95% CI 1.8-2.6, respectively) compared to Whites, but Black patients had lower risk than White patients (OR 0.8, 95% CI 0.6-0.9). Conclusions: Neutropenia remains a common side effect of CDKis, although the frequency of severe neutropenia is low. Of the three CDKis, P was associated with the highest rate of neutropenia.
Toxicity of concurrent and adjuvant temozolomide in patients with glioblastoma multiforme (GBM).
Authors: David Mcmahon, Awab Hussein, Hunter Mangleburg, Aine Nichianain, Orla Fitzpatrick, Ronan Andrew McLaughlin, Michael R. Conroy, Sam Jonathan Marks, Jarushka Naidoo, William Grogan, Adrian Gerard Murphy, Oscar S. Breathnach, Bryan T. Hennessy, Patrick G. Morris
Journal: Journal of Clinical Oncology (2022)

e14037 Background: (MGMT) promotor is prognostic and predictive of temozolomide (TMZ) benefit in newly diagnosed GBM. It has been suggested that MGMT methylation is associated with TMZ toxicity in some cancers such as melanoma but is not clearly defined in GBM. Methods: To investigate this, a retrospective electronic chart review of patients (pts) with resected GBM in a tertiary neurosurgical referral center from 1 July 2017 – 31 Dec 2020 was conducted. Hematological toxicities during TMZ with RT (concurrent) and subsequent TMZ (adjuvant) were assessed and graded by CTCAE V5.0. Toxicity was compared by MGMT methylation status. Results: In a 3.5 year period, 417 GBM resections were performed. Of these, 186 (45%) patients received at least 1 dose of TMZ in our institution: 180 pts received concurrent TMZ, 6 pts received adjuvant only. MGMT was methylated, unmethylated and unknown in 72, 97 and 17 pts respectively. In the concurrent and adjuvant phases respectively, thrombocytopenia incidence was 20%(N=14) and 52%(N=25) in the methylated group and 15%(N=15) and 51%(N=37) in the unmethylated group. In the adjuvant phase, incidence of ≥ grade 3 thrombocytopenia was 8%(N=4), in the methylated patients and 9%(N=7) for those unmethylated. Neutropenia incidence was low in the concurrent phase, however in the adjuvant phase was 29%(N=14) in the methylated group and 23%(N=17) in the unmethylated group. ≥G3 incidence was 10%(N=5) and 3%(N=2) respectively. Conclusions: In this retrospective study, a higher incidence of hematological toxicity was not seen in pts with MGMT methylated tumors. Methylation of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase.[Table: see text]
Impact of cancer diagnosis, stage, and systemic therapies on immunogenicity after COVID-19 vaccination in patients with cancer: A systematic review and meta-analysis.
Authors: Guilherme Nader Marta, Chloe Spilleboudt, Diogo Martins-Branco, Ana Tecic Vuger, Veronique Debien, Lieveke Ameye, Mariana Brandão, Kevin Punie, Angela Loizidou, Karen Willard-Gallo, Ahmad Awada, Martine J. Piccart-Gebhart, Evandro de Azambuja
Journal: Journal of Clinical Oncology (2022)

1537 Background: Patients (pts) with cancer are at increased risk of severe COVID-19. Both underlying malignancy and anti-cancer treatments influence the immune system, potentially impacting the level of vaccine protection achieved. Methods: A systematic literature search of PubMed, Embase, CENTRAL and conference proceedings (ASCO annual meetings and ESMO congress) up to 28/09/21, was conducted to identify studies reporting anti-SARS-CoV-2 spike protein immunoglobulin G seroconversion rates (SR) at any time point after complete COVID-19 immunization (mRNA- or adenoviral-based vaccines) in cancer pts. Complete immunization was defined as 1 dose of JNJ-78436735 vaccine or 2 doses of BNT162b2, mRNA-1273 or ChAdOx1 nCoV-19 vaccines. Subgroup analyses were performed to examine the impact of cancer diagnosis, disease stage, and anticancer therapies on the SR. Overall effects were pooled using random-effects models and reported as pooled SR with 95% confidence intervals (CI). Results: Of 1,548 identified records, 64 studies were included in this analysis reporting data from 10,511 subjects. The Table shows the SR in the overall population and specific subgroups. In pts with solid malignancies (SM), disease stage and primary site did not significantly impact the SR. In pts with hematologic malignancies (HM), SR were significantly lower in pts with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) compared to acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), and multiple myeloma (MM). Concerning the impact of cancer therapies on SR, pts with SM undergoing chemotherapy had numerically lower SR (N = 1,234, SR 87%, CI 81-92) compared to those treated with immune checkpoint inhibitors (N = 574, SR 94%, CI 88-97) or endocrine therapy (N = 326, SR 94%, CI 86-97) with or without another targeted therapy. Pts with HM treated with anti-CD20 therapy (within the last 12 months: N = 360, SR 7%, CI 2-20; or more than 12m: N = 175, SR 59%, CI 35-80), immune-modulating agents (BTK or BCL2 inhibitors) (N = 462, SR 47%, CI 32-64%) or other immunotherapies (anti-CD19/CART or anti-CD38) (N = 293, SR 37%, CI 23-53) had lower SR compared to pts treated with autologous (N = 353, SR 77%, CI 67-85) or allogenic stem cell transplantation (N = 509, SR 77%, CI 68-84). Conclusions: SR varies between cancer types and anticancer therapies with some cancer pts having low protection against COVID-19 even after complete vaccination. [Table: see text]
A pancancer analysis of <i>KRAS</i> alterations in Chinese population.
Authors: Yan Hou, Luyan Lou, Yanrui Zhang, Yun Zhang, Xiayuan Liang, Feng Lou, Shanbo Cao, Huina Wang
Journal: Journal of Clinical Oncology (2022)

e15127 Background: Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated oncogene in human cancers. Sotorasib (AMG 510) has shown promising anticancer activity in patients with heavily pre-treated KRAS p.G12C mutant solid tumors. Here, we provide an overview of genomic diversity of KRAS alterations in a large cohort of Chinese patients. Methods: Molecular profiles of 16,654 tumor specimens were obtained using gene-panel target-capture next-generation sequencing, and classified based on the presence and subtypes of KRAS mutation. Tumor mutation burdens (TMB) were calculated using an Acornmed panel with 808 cancer-related genes. Results: In total,15.04% (2505/16654) of pan-cancer patients harbored RAS mutations, and 13.58% (2262/16654) patients carried KRAS mutations in the current study. Five main subtypes of KRAS mutation were detected including G12D (642, 28.38%), G12V (392, 17.33%), G12C (354, 15.65%), G13 (220, 9.73%), G12A (101, 4.47%). In our cohort, the highest KRAS G12C mutation frequency tumor type was lung cancer (12.33%) followed by colorectal cancer (1.99%), which is comparable with the previously published data. Among all patients with KRAS G12C mutation, 77.40% (274/354) of the patients were male and 22.60% (80/354) were female. Tumor mutation burdens (TMB) were calculated for 151 samples of all the 352 KRAS G12C mutation samples. The median TMB was 10.15 mut/Mb with 50.99%≥10 mut/Mb and 14.57%≥20 mut/Mb. However, according to the results of CodeBreaK 100 exploratory analysis at the 2021 ASCO annual meeting, among all patients with KRAS G12C mutation, 17.86% of the patients had ≥ 10 mut /Mb, which was defined as TMB-high. Therefore, it can be found that the TMB of domestic and foreign patients is different. Conclusions: Genomic alterations in KRAS are widespread among Chinese pan-cancer patients. Results of CodeBreaK 100 exploratory analysis presented at the 2021 ASCO Annual Meeting showed no significant difference (40% vs 42%) in objective response rates between TMB high (≥ 10 mut/Mb) and TMB low (&lt; 10 mut/Mb). Based on our data, the threshold of TMB high in the Chinese population should be higher. The molecular marker exploration of AMG 510 efficacy in the Chinese population needs to be further carried out and confirmed.
A phase I trial of T-cell receptor gene therapy targeting KK-LC-1 for gastric, breast, cervical, lung and other KK-LC-1 positive epithelial cancers.
Authors: Scott Norberg, Erika Maria Von Euw, Gordon Parry, Steven Highfill, Zulmarie Franco, James L. Gulley, Christian S. Hinrichs
Journal: Journal of Clinical Oncology (2022)

TPS2678 Background: T cell receptor (TCR)-T cell therapy is an emerging cancer treatment strategy. Thus far, demonstration of clinical activity has been limited to a subset of solid tumors including melanoma, synovial cell sarcoma and HPV-associated cancer. It is estimated that metastatic epithelial cancers are responsible for approximately 90% of cancer deaths in the United States. The estimated 600,000 cancer deaths each year is driven largely by lung adeno- and squamous cell carcinoma and invasive breast cancer, which account for approximately 30% of all cancer-related deaths. Kita-Kyushu Lung Cancer Antigen 1 (KK-LC-1) is a cancer germline antigen with expression restricted to germ cells in adults and certain epithelial cancers including lung, breast, gastric and cervical. We identified a KK-LC-1 TCR from the tumor-infiltrating lymphocytes (TIL) of a patient with cervical cancer who had a complete tumor response to TIL therapy. The KK-LC-1 TCR was the most dominate clonotype in the infused TIL product and persisted in the peripheral blood following infusion, suggesting that it may have contributed to cancer regression in this patient. Methods: We are conducting a phase I cell dose escalation trial to test the safety and efficacy of KK-LC-1 TCR-T cell therapy in patients with metastatic KK-LC-1 positive epithelial cancer. Patients receive a lymphocyte depleting conditioning regimen followed by a one-time infusion of genetically engineered T cells expressing the KK-LC-1 TCR (KK-LC-1 TCR-T cells) and high-dose systemic aldesleukin. KK-LC-1 positivity is determined by RNAscope assay measuring the percentage of cancer cells expressing CT83 (gene encoding KK-LC-1) with a percentage of 25 or greater considered positive. Main inclusion criteria include HLA-A*01:01 allele, prior first-line therapy, ECOG of 0 or 1 and adequate organ and hematologic function. Main exclusion criteria include active major medical illness of the cardiovascular, respiratory or immune system, primary or secondary immunodeficiency and autoimmune disease. Participants will be entered in sequential dose levels and receive escalating doses of cells beginning at 1x10 8 and ending with 6x10 10 . Dose-limiting toxicities will be assessed during the first 30 days of cell infusion. The primary objective is to determine the maximally tolerated dose of KK-LC-1 TCR-T cells. Exploratory objectives include assessing the safety and efficacy of KK-LC-1 TCR-T cells and to conduct immunologic studies to understand and improve the administered treatment. Clinical trial information: NCT05035407.
Network analysis to determine association between immuno-related toxicities and immune soluble profile in patients treated with anti–PD-1.
Authors: Andrea Botticelli, Alessio Cirillo, Giulia Pomati, Enrico Cortesi, Ernesto Rossi, Giovanni Schinzari, Giampaolo Tortora, Silverio Tomao, Marianna Nuti, Giulia Fiscon, Lorenzo Farina, Simona Pisegna, Fabio Ciurluini, Antonella Chiavassa, Sasan Amirhassankhani, Alessandra Di Filippo, Ilaria Zizzari, Silvia Mezi, Paolo Marchetti
Journal: Journal of Clinical Oncology (2022)

2553 Background: Immune checkpoint inhibitors (ICIs) have peculiar, immune-related adverse events (irAEs), as a consequence of interfering with self-tolerance mechanisms. The incidence of irAEs varies by ICI class, administered dose and treatment schedule. The aim of the study was to define a baseline (T0) immune profile (IP) predictive of irAE development. Methods: A prospective, multicenter study evaluating the IP of 79 patients with advanced cancer, treated with anti-PD-1drugs as a first- or second-line setting was performed. The results were then correlated with irAEs onset. The IP was studied by means of multiplex assay, evaluating circulating concentration of 12 cytokines, 5 chemokines, 13 soluble immune checkpoints and 3 adhesion molecules. IDO levels were evaluated through a modified liquid chromatography–tandem mass spectrometry. Data were first pre-processed by performing logarithmic transformation and Shapiro-Wilk-test. A connectivity heatmap was obtained by calculating Spearman correlation coefficients. Two different networks of connectivity were constructed, based on the toxicity profile. Results: Toxicity was predominantly of low/moderate grade. High-grade irAEs were relatively rare, while cumulative toxicity was high (23%). A positive and statistically significant correlation between the cumulative toxicity and IP10 and IL8, sLAG3, sPDL-2 sHEVM, sCD137, sCD27 and sICAM1 was found. Moreover, patients who experienced irAEs had a markedly different connectivity pattern characterized by disruption of most of the paired connections between cytokines (all the connections of the cytokine IL8, most of the connections between the pro-inflammatory chemokines, or all the connections of CD137, CD27, and CD28), while sPDL-2 pair-wise connectivity values seemed to be intensified. Network connectivity analysis identified a total of 187 statistically significant interactions in patients without toxicity and a total of 126 interactions in patients with toxicity. Ninety-eight interactions were common to both networks, while 29 were specifically observed in patients with toxicity. Conclusions: A peculiar pattern of immune dysregulation in patients who develop irAEs was defined. This immune serological profile could lead to the design of a personalized therapeutic strategy in order to prevent, monitor and treat irAEs at an early stage.
Real-world data of durvalumab plus chemotherapy for extended stage small cell lung cancer patients: A Chilean experience.
Authors: Suraj Rajesh Samtani, Carlos Rojas, Jaime Gonzalez, Luis Godoy, Mauricio Burotto
Journal: Journal of Clinical Oncology (2022)

e20600 Background: Immunotherapy has changed the landscape for small cell lung cancer treatment. The aim of this study was to evaluate the efficacy of durvalumab plus chemotherapy in small cell lung cancer (SCLC) patients in real world experience. Methods: Eligibility criteria included, histologically confirmed extended stage SCLC (ES-SCLC), evaluable disease and no prior therapy. Patients received durvalumab plus chemotherapy until progressive disease (PD) or unacceptable toxicity. The main aim of the study was to report the efficacy and safety profile of durvalumab plus chemotherapy in patients with SCLC of our everyday clinical practice. The secondary aim was to perform subgroup analysis by clinical features. Results: From May 2020 to January of 2022, 15 patients were enrolled. The patients demographics were: median age 62 years, 67% male; 93,3% former/current smoker; 100% of patients presented with extended stage SCLC at diagnosis and 26,6% had brain metastasis at diagnosis. The most frequent sites of metastasis were distant lymph nodes 67%, liver metastasis 40% and bone metastasis 33%. Number of average cycles was 16,5. The median overall survival was 11,43 months and overall response rate (ORR) was 46%. In terms of safety profile, 73% developed treatment related adverse effects, 40% were grade 2 and 20% were grade 3. No treatment adverse effects leading to deaths were observed in our cohort of patients. Conclusions: This study represents one of the first real word experience with durvalumab plus chemotherapy in ES SCLC and the results are consistent with previously reported in clinical trials.
A phase 0/surgical window-of-opportunity study in progress, evaluating evolocumab in patients with high-grade glioma or glioblastoma.
Authors: Kirit Singh, Matthew Foster, Elizabeth S. Miller, Simon Gregory, Kent J. Weinhold, David M. Ashley, Annick Desjardins, Justin Low, Katherine B. Peters, Erin Severance, Denise Jaggers, Henry S. Friedman, Margaret O. Johnson, Allan H. Friedman, Stephen T. Keir, James Emmett Herndon, Chuan-Yuan Li, Peter E. Fecci, John H. Sampson, Mustafa Khasraw
Journal: Journal of Clinical Oncology (2022)

TPS2076 Background: High-grade gliomas (HGGs) are immunologically ‘cold’ tumors. This phenomenon is partly due to reduced expression of major histocompatibility class (MHC) I on the surface of tumor cells, which prevents CD8+ cytotoxic T lymphocyte activity (CTLs). Blockade of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases MHC class I expression, enhances CTL tumoral infiltration, and potentiates checkpoint inhibition in vivo. Evolocumab is an FDA-approved fully human IgG2 monoclonal antibody PCSK9 inhibitor which is clinically indicated for hyperlipidemia. This study seeks to determine whether evolocumab can cross the blood-brain barrier (BBB) and enhance MHC I expression on resected tumor cells, serving as a potential future adjunct for immunotherapy. Methods: This study will enroll ten patients over 18 years who have newly diagnosed or recurrent HGG. These patients will also need to be undergoing resection of their tumor as part of their planned treatment pathway. Following informed consent, patients will receive evolocumab (420mg, subcutaneously) 7-14 days before surgical debulking of the tumor. We will collect tissue which is not required for histological tumor analysis and compare it with a contemporaneous matched control cohort. This will consist of resected tumor specimens from patients not treated with evolocumab. Quantification of the drug will be performed using mass spectroscopy, flow cytometry, and single-cell sequencing. The primary objective of this study is to evaluate whether evolocumab can cross the BBB and be measured in resected tumor specimens taken from patients with HGG. Secondary objectives include an analysis of lipid metabolism and MHC-I expression on the tumor via flow cytometry and CITEseq. Wilcoxon rank-sum test or a two-sample t-test, will compare groups for these endpoints. Exploratory analyses will determine if evolocumab leads to changes in tumorigenic pathways and the immune profile of tumor infiltrating lymphocytes (TILs). Bioinformatic analyses will be performed using protein set enrichment, gene ontology (GO) annotations, and search tools from the retrieval of interactive genes/proteins (STRING). Progress: The study was activated on 10/04/2021 (NCT04937413) and at the time of submission has enrolled 5 participants (4 to control arm, 1 to intervention arm). Clinical trial information: NCT04937413.
Differential diagnosis of hematologic and solid tumors using targeted transcriptome and artificial intelligence.
Authors: Hong Zhang, Maher Albitar, Muhammad Asif Qureshi, Mohsin Wahid, Ahmad Charifa, Aamir Ehsan, Andrew Ip, Ivan De Dios, Wanlong Ma, James McCloskey, Michele Donato, David Samuel DiCapua Siegel, Martin Gutierrez, Andrew L Pecora, Andre Goy
Journal: Journal of Clinical Oncology (2022)

3018 Background: Diagnosis and classification of tumors is becoming increasingly dependent on biological and molecular biomarkers. RNA expression profiling using next generation sequencing (NGS) provides information on various biological and molecular changes in the cancer and in the microenvironment. We explored the potential of using targeted transcriptome and artificial intelligence (AI) in the differential diagnosis and classification of various hematologic and solid tumors. Methods: RNA from hematologic neoplasms (N = 2606) and solid tumors (N = 2038) as well as normal bone marrow and lymph node control (N = 806) were sequenced by NGS using a targeted 1408-gene panel. The hematologic neoplasms included 20 different subtypes. Solid tumors included 24 different subtypes. Machine learning is used for comparing two classes at a time. Geometric Mean Naïve Bayesian (GMNB) classifier is used to provide differential diagnosis across 45 diagnostic entities with assigned ranking. Results: Machine learning showed high accuracy in distinguishing between two diagnoses with AUC varied between 1 (Sarcoma vs GIST) and 0.841 (MDS vs normal control) (examples in Table). For differential diagnosis between all 45 different diagnoses, we used 3045 samples for training the GMNB algorithm and 1415 samples for testing. Correct first choice diagnosis was obtained in 100% of ALL, 88% of AML, 85% of DLBCL, 82% of colorectal cancer, 88% of lung cancer, 72% of CLL, and 72% of follicular lymphoma. The algorithm had difficulty in typically overlapping diagnoses and diagnosed as first choice 19% of MDS, 46% of normal, and 12% of MPN. Diagnosis improved significantly when second choice was considered. Conclusions: Targeted RNA profiling with proper AI can provide highly useful tools for the pathologic diagnosis and classification of various cancers. Additional information such as mutation profile and clinical information can improve these algorithms, reduce subjectivity, and minimize errors in pathologic diagnoses. [Table: see text]